When a patient experiences significant pain as the result of a serious traumatic injury, a surgical procedure, or chronic illness (e.g., cancer), relief requires strong medication under a doctor's prescription. Opiate drugs are a class of pain-relieving prescription drugs frequently prescribed for moderate to severe pain. The opioids are a group of drugs, both natural and synthetic, that are employed primarily as centrally-acting analgesics and are opium or morphine-like in their properties (Gilman et al., 1980, GOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Chapter 24:494-534, Pergamon Press; hereby incorporated by reference). The opioids include morphine and morphine-like homologs, including, e.g., the semisynthetic derivatives codeine (methylmorphine) and hydrocodone (dihydrocodeinone), among many other such derivatives. Morphine and related opioids exhibit agonist activity in the central nervous system (CNS) (referring to the brain and spinal cord) at p (mu) opioid receptors, as well as showing affinity for the ō (delta) and κ (kappa) opioid receptors, to produce a range of effects including analgesia, drowsiness, and changes in mood, among others. In addition to potent analgesic effects, the morphine-related opioids may also use a number of undesirable effects, including, for example, nausea, vomiting, dizziness, mental clouding, dysphoria, pruritus, constipation, increased biliary tract pressure, urinary retention, hypotension and, most notably, respiratory depression.
Opioids depress all phases of respiratory activity to some extent. Respiratory depression becomes significant when it leads to the need for medical intervention. Opioids interfere with carbon dioxide chemoreceptors in the medulla leading to increased retention of carbon dioxide. The increase in carbon dioxide levels does not stimulate a concomitant increase in respiratory rate; thus, the body is forced to rely on a less sensitive oxygen-driven respiration-regulating mechanism. Respiratory depression may be treated by artificial ventilation or be reversed by administration of chemical agents such as naloxone. Naloxone will immediately reverse opioid-induced respiratory depression, but the dose may have to be repeated due to the short duration of action of naloxone. More importantly, naloxone will also antagonise the analgesic effect, thus negating the primary clinical purpose of administration of the opioid.
Patients with respiratory illness, whether diagnosed or undiagnosed, represent a significant subpopulation of patients requiring pain management with opiates for reasons unrelated to their respiratory illness. Patients with compromised lungs (i.e., with respiratory illnesses) are at increased risk for opiate induced respiratory depression and/or cessation because of their impaired respiratory capability. Respiratory depression is a decrease in the rate or depth of respiratory effort and a resulting decrease in level of alertness.
Respiratory illnesses with increased susceptibility to opiate-induced respiratory depression and/or cessation include infectious or inflammatory conditions such as asthma, bronchiectasis, pulmonary tuberculosis, chronic obstructive pulmonary disease, bronchitis, bronchopneumonia, chronic laryngitis, chronic sinusitis, emphysema, fibrosing alveolitis, idiopathic pulmonary fibrosis and sarcoidosis. Neoplastic diseases of the lung also are included, for example, non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, large cell carcinoma, undifferentiated carcinoma, small cell lung cancer, oat cell cancer and mesothelioma—
Du Bose and Berde (Technical Corner, International Association for the Study of Pain Newsletter, July/August, 1997) provide a number of specific examples of the importance of respiratory depression in patient groups as follows. Respiratory depression can occur in circumstances where the duration of an opioid's analgesic and respiratory depressant effects outlasts the duration of a painful stimulus. For example, a burn dressing change or a bone marrow aspiration may be intensely painful for only a brief time. An opioid such as morphine, which has comparatively slow onset and prolonged duration, may be titrated to give an appropriate degree of analgesia and sedation. However, excessive sedation and respiratory depression may occur following the procedure when respiratory stimulation declines along with a rapid reduction in the intensity of pain and distress. This complication can be prevented in most circumstances by constant observation, awakening the patient, and encouraging deep breathing until the opioid's effects dissipate. Even modest doses of opioids in awake subjects can have dramatic effects on the ventilatory response to hypoxemia. While depression of ventilatory responses to hypoxemia is of little consequence to most healthy subjects, the consequences can be severe in patients who may be dependent on hypoxic respiratory drive, such as those with chronic obstructive pulmonary disease (COPD) and long-standing hypercapnia. Also, certain disease states may increase respiratory risks from the administration of opioids. For example, disorders of neural tube development, including spina bifida, can be associated with abnormal respiratory control, even in patients with mild degrees of neurologic impairment. The use of opioids in these high-risk groups may require more judicious dose titration and closer observation. Morbidly obese and Pickwickian patients may have difficulties with opioid dose titration. Patient-controlled analgesia (PCA) use in obese postoperative patients showed as much as a 10-fold difference in opiate requirements.
DuBose and Berde (ibid.) further note that while pain antagonizes opioid-induced respiratory depression, sleep can intensify the depressant effects of opioids. During normal respiration, subatmospheric pressure in the pharynx tends to draw the tongue against the palate, narrowing the airway. The finely coordinated contraction of the tongue (especially the genioglossus) and pharyngeal musculature helps to maintain airway patency and prevent snoring or inspiratory collapse of the airway. Sleep and opioids separately, and in concert, depress genioglossus and pharyngeal muscle tone and diminish airway protective reflexes. Critical incidents from opioid-induced respiratory depression appear to be more common in the hours from midnight to 6 a.m., which is of more critical importance due to the lessened level of scrutiny of possibly affected patients during night time hours.
Depression of level of consciousness is an extremely useful guide to observing clinical effect in patients receiving opioids. Respiratory depression is almost always preceded by sedation or clouded sensorium. It has also been noted that abdominal surgery is associated with postoperative sleep disturbance. Also sleep disturbance and episodic hypoxemia are extremely common in patients receiving opioids following surgery. REM sleep is typically suppressed initially, and then a rebound increase in REM sleep often occurs on the second and third postoperative nights. It has been suggested that opioids contribute to disturbed sleep postoperatively.
Perhaps the respiratory illnesses presenting the greatest concern are those conditions which, by definition, involve a major defect in respiratory control, most particularly in sleep disordered breathing such as sleep apnea syndrome (SAS).
Sleep apnea syndrome (SAS) is a breathing disorder characterized by apneas and hypopneas. Apneas are a cessation of airflow for ten seconds or more and hypopnea: a decrease in flow by at least 50% for 10 seconds or more. Both apneas and hypopneas are associated with sleep arousal and/or oxygen desaturations of 3% or more. Apneas and hypopneas result from upper airway occlusion, either full or partial, or from a loss of or a significant decrease in the autonomic drive to breathe. There are three types of apnea: obstructive, central, and mixed. Obstructive sleep apnea (OSA) is the most common type of sleep apnea. OSA occurs when the upper airway occludes (either partially or fully) but efforts to breathe continue. The primary causes of upper airway obstruction are lack of muscle tone during sleep, excess tissue in the upper airway, and anatomic abnormalities in the upper airway and jaw. Central sleep apnea (CSA) affects only 5-10% of the sleep apnea population. CSA occurs when both airflow and respiratory effort cease. This cessation of breathing results from a loss of the autonomic drive to breathe. Mixed apneas occur when an initial central component followed by an obstructive component causes a cessation of breathing. In the absence of formal sleep studies, the diagnosis can be made clinically by interviewing patients and their sleeping partners. Clinical signs include loud snoring, observed apneic episodes, and excessive daytime somnolence.
The cause of upper airway obstruction in SAS patients was long thought to be the tongue, but fluoroscopy during sleep has shown this is rarely the case. The oropharynx itself is the most collapsible segment of the upper airway and the most likely site of obstruction. Physiologic studies have demonstrated that patients with SAS have narrowed upper airways to start with, so they are more susceptible than other patients to drugs or anesthetics that suppress pharyngeal muscle tone.
In normal, awake patients, there is a phasic activity of the pharyngeal muscles that contracts them immediately before inspiration, helping to resist the negative pressure generated by the diaphragm and keeping the airway from collapsing. This phasic pharyngeal contraction is markedly reduced both by REM sleep and by opiate administration. Patients with sleep apnea appear to be much more sensitive than normal individuals, even to minimal levels of sedation. The increased sensitivity of their hypoglossal nerves to low doses of anesthesia has been well described.
This increased tendency to airway obstruction can occur out of proportion to the level of sedation the opiates achieve. This would explain why many of the patients complained of significant pain shortly before falling asleep and developing obstructive episodes. Apneic episodes can occur with all routes of opioid administration. This increased sensitivity of SAS patients to opiates may be impossible to reverse with antagonists. One well-documented case in the literature described an obese patient who became comatose after a minimal dose of meperidine given intramuscularly as a premedication. Neither the airway obstruction nor the obtundation could be satisfactorily reversed with naloxone. When the patient had spontaneously recovered, his physicians ordered a sleep study, which confirmed the diagnosis of sleep apnea. This patient had a documented decrease in arterial pot to 30 mm Hg spontaneously during sleep associated with multiple PVC's and episodes of sinus bradycardia. Had this not been noticed intraoperatively, it might have happened unmonitored on the ward.
On a daily basis, surgical patients are wheeled into operating rooms with unrecognized obstructive sleep apnea (OSA). Diagnosed OSA patients, as well as undiagnosed patients who present with classic signs and symptoms, are at risk for significant post-operative respiratory complications after receiving a general anesthetic and postoperative opiate analgesia. Yet health care providers frequently fail to screen for OSA, and when it is suspected or diagnosed, often fail to incorporate this information into the perioperative plan of care. Approximately 9% of women and 24% of men ages 30 to 60 have apnea/hypopnea episodes. Additionally, it has been estimated that 80% to 90% of patients with OSA are undiagnosed.
The administration of opiate pain medication in patients with sleep apnea syndrome must be closely monitored. One problem observed by physicians was that pain medication orders for any given patient might be written by different individuals (surgeon, anesthesiologist, or primary care practitioner), not all of whom may be aware of the diagnosis of OSA. Clearly, wider understanding of this syndrome is crucial, and suggestions included red-flagging the charts of these patients to warn of the risks of opiate usage.
Farney et al. (Chest 203: 632-639 (2003)) described three patients who illustrate distinctive patterns of sleep-disordered breathing who are receiving long-term, sustained-release opioid medications. Polysomnography shows respiratory disturbances occur predominantly during non-rapid eye movement (NREM) sleep and are characterized by ataxic breathing, central apneas, sustained hypoxemia, and unusually prolonged obstructive “hypopneas” secondary to delayed arousal responses. In contrast to what is usually observed in subjects with obstructive sleep apnea (OSA), oxygen desaturation is more severe and respiratory disturbances are longer during NREM sleep compared to rapid eye movement sleep. Further they noted that is these patients treatment with a nasal CPAP (continuous positive airway pressure) device without supplemental oxygen was ineffective. They conclude that opioids could interfere with providing effective nasal CPAP treatment and that there is potential for harm because patients with OSA syndrome continue to be under-diagnosed while at the same time the use of opioids for chronic pain control continues to increase.
As pain is treated more aggressively, the tragic complication of respiratory arrest in patients with sleep apnea syndrome and other respiratory illnesses may be seen more frequently.
At present, it is impossible to imagine major postoperative and post-traumatic pain relief without opioid therapy. It would be highly desirable if therapies were available that provided adequate and satisfactory pain relief with a minimum of respiratory risk in inducing severe respiratory depression, episodes of sleep apnea and/or complete cessation of respiration.